title: Chronic cocaine dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling.
abstract: Dopamine increases triggered by cocaine and consequent stimulation of dopamine receptors (including D1 and D2) are associated with its rewarding effects. However, while facilitation of D1 receptor (D1R) signaling enhances the rewarding effects of cocaine, facilitation of D2R signaling decreases it, which indicates that for cocaine to be rewarding it must result in a predominance of D1R over D2R signaling. Moreover, the transition to compulsive cocaine intake might result from an imbalance between D1R and D2R signaling. To test the hypothesis that chronic cocaine use unbalances D1R over D2R signaling during cocaine intoxication, we used microprobe optical imaging to compare dynamic changes in intracellular calcium ([Ca(2+)]i, marker of neuronal activation) to acute cocaine in striatal D1R-EGFP and D2R-EGFP-expressing neurons between control and chronically treated mice. Chronic cocaine attenuated responses to acute cocaine in D1R (blunting Ca(2+) increases by 67 ± 16%) and D2R (blunting Ca(2+) decrease by 72 ± 17%) neurons in most D1R and D2R neurons (~75%). However, the dynamics of this attenuation during cocaine intoxication was longer lasting for D2R than for D1R. Thus, whereas control mice showed a fast but short-lasting predominance of D1R over D2R signaling (peaking at ~8 min) during acute cocaine intoxication, in chronically treated mice D1R predominance was sustained for >30 min (throughout the measurement period). Thus, chronic cocaine use dramatically reduced cocaine-induced DA signaling, shifting the balance between D1R and D2R signaling during intoxication to a predominance of D1R (stimulatory) over D2R (inhibitory) signaling, which might facilitate compulsive intake in addiction.
authors.affiliation: Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, and National Institute of Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Kicheon
authors.initials: K
authors.lastname: Park
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Yingtian
authors.initials: Y
authors.lastname: Pan
authors.forename: Congwu
authors.initials: C
authors.lastname: Du
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine; D002118:Calcium; D004298:Dopamine